One of the most prominent characteristics of tumors is their abnormal vasculature. Constantly stimulated by angiogenic factors in the tumor environment, newly formed blood vessels fail to develop into a fully mature and functional vascular network. In recent years, we have begun to recognize the biological and clinical significance of the deficiency in maturation and the poor functionality of tumor blood vessels. Through improvement of the circulation within the tumor, normalization of such structurally and functionally abnormal tumor vasculature may significantly improve drug delivery and enhance the efficacy of conventional cytotoxic therapies. The long term goal of this study is, therefore, to understand the molecular mechanism of maturation and normalization of pathologically regenerating vasculature in the tumor. Our recent studies suggest that a small GTPase, R-Ras, promotes vessel maturation through induction of endothelial quiescence and facilitation of the formation of basement membrane and the sheath of pericytes enwrapping the nascent vessels. In this proposal, we will determine the role of R-Ras in regulating the maturation of tumor microvessels in vivo, analyze the cellular mechanism of this regulation in vitro, and determine the therapeutic significance of R-Ras-mediated vessel maturation in cancer using an R-Ras-null mouse model. In Aim 1, we will investigate the effect of R-Ras deficiency on the structural and functional integrity of tumor microvessels in vivo. In Aim 2, we will conduct in vitro analysis of the effect of R-Ras on endothelial cell activities related to the vessel maturation process (e.g. formation and stabilization of adherent junction to reduce vessel leakiness). We will also determine the role of R-Ras in pericyte regulation, including the role in endothelial-pericyte interaction, as this interaction is essential for the differentiation and functional maturation of both cell types. In Aim 3, we will investigate how R-Ras affects the tumor progression and the therapeutic efficacies of cytotoxic treatments through promoting maturation of tumor vasculature. In this aim, we will also determine whether the normalization of tumor vasculature induced by antiangiogenic therapy and its clinical benefit are linked to the expression of R-Ras in the affected vessels. The findings from these studies could provide the rationale for design of effective cancer regimens. PUBLIC HEALTH RELEVANCE: Blood vessels develop abnormally in tumors. Due to this abnormality, malignant tumors lack adequate circulation, hindering the delivery of therapeutic agent to the tumors. This application proposes to investigate how we could manipulate the blood vessel network within the tumor in order to enhance tumor responses to chemotherapeutic or radiation treatments for cancer.